Dose dependent cephaloridine-induced renal tubular necrosis was observed in mice, rats, and rabbits following a single i.p. injection of cephaloridine. Necrosis was prevented, but nor reversed, by prior treatment with inhibitors of drug metabolism such as piperonyl butoxide and cobaltous chloride, suggesting that the nephrotoxicity of this cephalosporin antibiotic may be mediated by metabolic activation to a chemically reactive species. Necrosis was potentiated by the concomitant administration of aminoglycoside antibiotics and by diethyl maleate, a depletor of hepatic and renal glutathione. Experimental attempts to demonstrate covalent binding of cephaloridine metabolites to renal proteins in vivo and renal microsomal protein in vitro were rendered uninterpretable by facile exchange of label from the radioisotope employed. Studies are in progress to define further the role of metabolic activation in cephalosporin-induced nephrotoxicity and the mechanistic basis for aminoglycoside enhancement of toxicity.